title: Expression of leucine-rich repeat kinase 2 (LRRK2) inhibits the processing of uMtCK to induce cell death in a cell culture model system.
abstract: PD (Parkinson's disease) is the most common neurodegenerative movement disorder. Mutations in LRRK2 (leucine-rich repeat kinase 2) gene are linked to the most common inherited and sporadic PD. Overexpression of LRRK2 and its mutants could induce mitochondrial-dependent neuronal apoptosis. However, the underlying mechanism remains elusive. We have identified several novel LRRK2 interacting proteins and showed that LRRK2 can interact with three components of the PTPC (permeability transition pore complex) including ANT (adenine nucleotide translocator), VDAC (voltage-dependent anion channel) and uMtCK [ubiquitous MtCK (mitochondrial creatine kinase)]. Those components have been reported to be involved in the permeability of mitochondrial membrane. We provide evidence that LRRK2 is likely to interact with uMtCK directly and expression of LRRK2 and its mutant form can suppress the processing of the immature form of uMtCK. LRRK2 expression keeps the uMtCK preprotein on the outer mitochondrial membrane instead of entering the mitochondria. In addition, the expression of both wild-type and mutant forms of LRRK2 promotes the interaction between ANT and VDAC, which plays a role in permeabilization transition pore opening. Finally, LRRK2-induced cell death can be suppressed by uMtCK. Our findings imply that LRRK2 can interact directly with uMtCK to block its entry into mitochondria and its subsequent processing, resulting in inhibition of mitochondrial energy channelling. Meanwhile, the decrease of uMtCK in mitochondria results in elevated interaction between ANT and VDAC and leads to neuronal apoptosis. Thus, our study provides the rational for clinical trials using creatine to treat PD and supports the notion of exploiting LRRK2 as a drug target for PD.
authors.affiliation: *The Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cui
authors.forename: Mei
authors.initials: M
authors.lastname: Yu
authors.affiliation: *The Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Niu
authors.affiliation: ‡Departments of Neurology and Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Yue
authors.affiliation: *The Key Laboratory of Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D052281:Creatine Kinase, Mitochondrial Form / Q000378:metabolism*; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D010300:Parkinson Disease / Q000201:enzymology / Q000473:pathology; D054730:Protein Interaction Domains and Motifs; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism
chemical_list: D050994:Voltage-Dependent Anion Channels; D000226:Mitochondrial ADP, ATP Translocases; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D052281:Creatine Kinase, Mitochondrial Form